Bruton's tyrosine kinase (BTK) is a key regulatory enzyme in B-cells, mast cells, and platelets. The ability of B-cells to appropriately respond to antigen has been shown to be dependent on the enzymatic activity of BTK. Similarly, IgE-receptor mediated leukotriene synthesis and release in mast cells is dependent on BTK. BTK is also critical for collagen-induced aggregation of platelets. BTK promotes the survival and drug resistance of leukemia and lymphoma cells. Finally, BTK is required for radiation-induced apoptosis (Ucken et al. 1996, Science, 273:1096-1100). Thus, BTK inhibitors have potential for treatment and prevention of various pathologic health conditions due to their activity, for example:
Inhibition of B-cells by BTK Inhibitors: Because of the vital role of BTK in B-cells, BTK inhibitors can be used to inhibit B-cell function and/or to induce B-cell death or apoptosis. Thus, BTK inhibitors are useful in the treatment and inhibition of B-cell mediated autoimmune diseases such as Lupus, B-cell mediated organ transplant rejection (especially xenotransplantation), B-cell mediated drug reactions (anaphalactic shock and the like), B-cell mediated immune-complex disorders, and B-cell mediated resistance to drugs and other treatment agents (neutralizing antibodies to immunotoxins or L-asparaginase in cancer patients, Factor VIII antibodies in hemophiliacs, and the like).
Inhibition of mast cells by BTK inhibitors: Because of the vital role of BTK in mast cells, BTK inhibitors can be used to inhibit mast cell function and/or to induce mast cell death. Thus, BTK inhibitors are useful to treat mast-cell mediated disorders, including allergic and inflammatory disorders (asthma, arthritis, inflammatory bowel disease, and the like).
Inhibition of platelet aggregation by BTK inhibitors: Because of the role of BTK in platelets, BTK inhibitors can be used to inhibit platelet function. Thus, BTK inhibitors are useful to treat or prevent thromboembolic conditions, abnormal platelet aggregation in the context of sepsis, atherosclerosis, vascular injury, and the like.
Inhibition of BTK in leukemia and lymphoma cells: BTK inhibitors can be used to promote apoptosis and reduce drug resistance in leukemia and lymphoma cells.
Inhibition of BTK in B-cell during radiation therapy: BTK inhibitors can be used to prevent undesired immunosuppression during radiation therapy by preventing radiation-induced death of B-cells.
Accordingly, novel inhibitors of BTK and methods for inhibiting BTK are needed for therapeutic use.